Drosophila Crumbs prevents ectopic Notch activation in developing wings by inhibiting ligand-independent endocytosis
Drosophila Crumbs prevents ectopic Notch activation in developing wings by inhibiting ligand-independent endocytosis
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DOI：
10.1242/dev.141762
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发表时间：
2016-12-01
期刊：
影响因子：
4.6
通讯作者：
Knust, Elisabeth
中科院分区：
文献类型：
--
作者：
Nemetschke, Linda;Knust, Elisabeth
许多信号传导组分在上皮细胞中受到顶端限制，并且受体定位和丰度是形态发生和组织稳态的关键。因此，控制顶基上皮极性对于正确的信号传导至关重要。Notch是一种普遍表达的、位于顶端的受体，它执行过多的功能;因此，它的活性必须受到严格的调控。在这里，我们表明，果蝇Crumbs，一个进化上保守的极性决定因素，通过两种蛋白质之间的直接相互作用，防止Notch内吞作用在发展中的翅膀。在不存在Crumbs的情况下，Notch内吞作用导致配体非依赖性、Deltex依赖性Notch信号传导途径的激活，并且不需要配体Delta和Serrate或γ-分泌酶活性。Crumbs的这种功能不是由于顶基极性的一般缺陷，因为其他顶端蛋白质的定位不受影响。我们的数据揭示了一种机制来解释Crumbs如何直接控制有效Notch受体的定位和贩运，并增加了Crumbs在Notch途径活性中的另一个调节方面。此外，我们的数据突出了顶端决定因素Crumbs，受体贩运和组织稳态之间的密切联系。
Many signalling components are apically restricted in epithelial cells, and receptor localisation and abundance is key for morphogenesis and tissue homeostasis. Hence, controlling apicobasal epithelial polarity is crucial for proper signalling. Notch is a ubiquitously expressed, apically localised receptor, which performs a plethora of functions; therefore, its activity has to be tightly regulated. Here, we show that Drosophila Crumbs, an evolutionarily conserved polarity determinant, prevents Notch endocytosis in developing wings through direct interaction between the two proteins. Notch endocytosis in the absence of Crumbs results in the activation of the ligand-independent, Deltex-dependent Notch signalling pathway, and does not require the ligands Delta and Serrate or gamma-secretase activity. This function of Crumbs is not due to general defects in apicobasal polarity, as localisation of other apical proteins is unaffected. Our data reveal a mechanism to explain how Crumbs directly controls localisation and trafficking of the potent Notch receptor, and adds yet another aspect of Crumbs regulation in Notch pathway activity. Furthermore, our data highlight a close link between the apical determinant Crumbs, receptor trafficking and tissue homeostasis.